Risperidone, which is the generic name for the compound of formula (I), 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, is a potent antipsychotic agent, especially useful for treating schizophrenia:

There have been reported a number of methods for risperidone synthesis but these methods generally suffer from the problems of low yield and complicated procedures.
For example, the benzisoxazol derivative of formula (E) obtained by ring closure of the oxime derivative of formula (II) is coupled with the pyrimidine derivative of formula (IV) to give risperidone, as shown in Scheme 1.

In Scheme 1, the coupling reaction of the benzisoxazol derivative (III) and the pyrimidine derivative (IV) may be performed by the method disclosed in U.S. Pat. No. 4,804,663, wherein the coupling reaction is performed in N,N-dimethylformamide in the presence of a sodium iodide catalyst (way a). However, this method gives a low yield of about 46% (overall yield of about 35%) due to the occurrence of side reactions such as self-polymerization of the benzisoxazol derivative (III).
Alternatively, the coupling reaction may be carried out using the method, International Publication No. WO 01/85731 which uses water as solvent instead of N,N-dimethylformamide so as to suppress the side reactions (way b). However, this method also gives an overall yield of only 55%.
Korean Patent Publication No. 96-9435, on the other hand, discloses a method as illustrated in Scheme 2, wherein the compound of formula (V) obtained by coupling of the oxime derivative of formula (II) with the pyrimidine derivative of formula (IV) is subjected to ring closure in the presence of a strong base such as sodium hydride.

However, this method still has a problem in that the overall yield is only 45%. In addition, this method has to deal with the risk of sodium hydride explosion.
Further, Spanish Patent No. 2,050,069 discloses a method for preparing risperidone which is described in Scheme 3: the compound of formula (VII) obtained by coupling of the benzoylpiperidine derivative of formula (VI) and the pyrimidine derivative of formula (IV) is subjected to oximation to give the compound (V), and ring closure thereof gives risperidone.

This method also gives a low coupling yield of 63%, and complicated work-up procedures are required.
Spanish Patent No. 2,074,966 describes a method of preparing risperidone as presented in Scheme 4, wherein the risperidone of formula (I) is obtained by the reaction of the oxazol derivative of formula (IX) and the aminopyridin derivative of formula (VIII).

However, this method is hampered by the problem that the processes of preparing the starting materials of formula (VIII) and (IX) are complicated.